Harnessing the mesenchymal stem cell secretome for the treatment of cardiovascular disease

Abstract

The broad repertoire of secreted trophic and immunomodulatory cytokines produced by mesenchymal stem cells (MSCs), generally referred to as the MSC secretome, has considerable potential for the treatment of cardiovascular disease. However, harnessing this MSC secretome for meaningful therapeutic outcomes is challenging due to the limited control of cytokine production following their transplantation. This review outlines the current understanding of the MSC secretome as a therapeutic for treatment of ischemic heart disease. We discuss ongoing investigative directions aimed at improving cellular activity and characterizing the secretome and its regulation in greater detail. Finally, we provide insights on and perspectives for future development of the MSC secretome as a therapeutic tool.

Figure 1. A Proposed Approach for Small Molecule-mediated Regulation of the MSC Secretome

(A) Conditioning MSC with small molecules can be utilized to stimulate the production of a customized secretome that can be optimized and characterized in vitro. (B) The effect of small molecule-conditioning of MSCs can be tested under highly dynamic, simulated conditions, mimicking microenvironments before and after the onset of MI and this may include co-culture assays with hypoxic cardiomyocytes and inflammatory cells. Pro-inflammatory cytokines such as TNF-α and IL-6 can be introduced to an MSC culture, for example, and MSC secreted factors (in blue) such as sTNFR1 and IL-10 can be tracked, in addition to their ability to modulate release of inflammatory cytokines from activated leukocytes. MSCs may secrete molecules such as IDO and PGE₂ that induce leukocytes to produce anti-inflammatory cytokines such as IL-10 that attenuates the effects of activated leukocytes and inhibits the pro-inflammatory activity of constitutively secreted IL-6 (from MSCs) and/or IL-6 already expressed in the myocardium. Likewise, towards attenuating pathological remodeling, one can test if small molecules can boost MSC secretion of TIMP-1 to inhibit ECM degrading proteases such as MMP-9. In addition to paracrine effects, conditioned MSCs may act through autocrine signaling to improve cell survival in hypoxic conditions.

Figure 2. A Proposed Engineering Solution for Sustaining a Customized MSC Secretome In Vivo and Facilitating Cardiovascular Repair

Bioengineering strategies may be employed to control and sustain the expression of the customized MSC secretome through smart biomaterials-based, intra- and/or extra-cellular, controlled release of stimulating molecules. MSCs, either as single cells or aggregates may be systemically infused or locally transplanted to facilitate cardiovascular repair with greater control over cell fate and function.